Estrogenic hormones are of primary importance in the female reproductive cycle and also play a role in mammary cancers. Estradiol is a potent, naturally occurring form of estrogen which may be associated with certain breast cancers. Estriol, related to estradiol, but differs in the respect that estradiol is the most potent naturally occurring estrogen whereas, estriol is a metabolite of and is considerably less potent than estradiol. Estriol is usually the predominant estrogenic metabolite found in urine and may be related to fetal distress. Accordingly, the detection of estriol serum levels in pregnant women provides information on fetal status during pregnancy. The clinical significance of estrogenic hormones is discussed by K. S. McCarty et al in Regulatory Mechanisms in Breast Cancer, Chapter 9, Kluwer Academic Publishers, Boston, 1991.
The synthesis of 6.alpha.-substituted estradiol analogs is discussed by Hamacaher et al in Arzneurn Forsch./Drug Res., 33 (1), 347-352 (1983), Frei et al in J. Steroid Biochem., 32 (2), 251-57 (1989), Nambura et al in Chem. Pharm. Bull., 22 (5), 1167-1173 (1974) and Jeffcoate et al in Steroids, 19 (2), 181-188 (1972).
The preparation of compounds 2 and 3 of scheme 1 herein is described by Dean et al in Steroids, 593-603 (1971), Longwell et al in Biol. Chem., 133, 219-299 (1940) and Burows et al in J. Org. Chem., 37, 4000 (1972).